Process for the 9(11)-enolisation of a steroid 1,4-diene-3,11-dione

ABSTRACT

A PROCESS FOR THE SELECTIVE 3- OR 9(11)-ENOLISATION OF A STEROID 1,4-DIENE-3,11-DIONE WHEREIN THE 1,4-DIENE-3,11DIONE IS TREATED UNDER SUBSTANTIALLY OXYGEN-FREE AND ANHYDROUS CONDITIONS IN A NON-HYDROXYLIC SOLVENT WITH AN ALKALI METAL BASE, OTHER THAN A LITHIUM BASE, WHICH IS SOLUBLE IN THE SOLVENT. WHERE THE 9(11)-ENOLATE IS DESIRED, THE DIONE IN NON-ENOLIZED FORM IS ALLOWED TO REACT WITH THE 3-ENOLATE INITIALLY FORMED, AND WHEN THE 3-ENOLATE IS REQUIRED THE REACTION IS EITHER CARRIED OUT BELOW -50* C., OR THE REACTION IS CARRIED OUT IN SUCH A MANNER THAT CONTACT BETWEEN THE 3-ENOLATE AND UNREACTED DIONE IS REDUCED OR AVOIDED. THE RESULTING 3- OR 9(11)-ENOLATES CAN BE CONVERTED TO THE CORRESPONDING ESTERS, AND EITHER THE ENOLATES OR THE CORRESPONDING ESTERS CAN BE HALOGENATED WHEREBY A HALOGEN IS INTRODUCED AT THE 6- OR 9POSITION RESPECTIVELY.

United States Patent O M 3,705,893 PROCESS FOR THE 9(11)-ENOLISATION OFA STEROID 1,4-DlENE-3,11-DIONE Derek Harold Richard Barton, London,England, as-

iignor to Research Institute for Medicine and Chemistry N Drawing. FiledNov. 23, 1970, Ser. No. 92,216 Claims priority, application GreatBritain, Nov. 24, 1969, 57,425/ 69 Int. Cl. C07c 173/06 US. Cl.260-23955 D Claims ABSTRACT OF THE DISCLOSURE A process for theselective 3- or 9(ll)enolisation of a steroid 1,4-diene-3,11-dionewherein the 1,4-diene-3,11- dione is treated under substantiallyoxygen-free and an hydrous conditions in a non-hydroxylic solvent withan alkali metal base, other than a lithium base, which is soluble in thesolvent. Where the 9(ll)enolate is desired, the dione in non-enolizedform is allowed to react with the 3-enolate initially formed, and whenthe 3-enolate is required the reaction is either carried out below -50*C., or the reaction is carried out in such a manner that contact betweenthe 3-enolate and unreacted dione is reduced or avoided. The resulting3- or 9(ll)enolates can be converted to the corresponding esters, andeither the enolates or the corresponding esters can be halogenatedwhereby a halogen is introduced at the 6- or 9- position respectively.

This invention relates to the preparation of steroid enolates and ofesters derived therefrom.

Steroid 1,4diene-3,11-diones are frequently encountered among thephysiologically active steroids, especially the corticosteroids, and itis oten found that the derivatives carrying substituents at the 6- or9-position possess enhanced activity. Thus, for example,9e-fiuoro-16/3-methylprednisone (betamethasone) possesses greateranti-inflamrnatory activity than 16 8-methyl prednisone and 6- methylprednisone also exhibits greater activity than prednisone. Insynthesising these compounds, the 6- or 9- substituent is usuallyintroduced at a relative early stage, before the 1,4-diene-3,l1-dionesystem is formed but considerable difiiculty has been experienced insubstituting at the sterically hindered 9-position.

We have now found that a 6- or a 9'-substituent can be introduced intoan existing steroid l,4-diene-3,ll-dione by selectively forming the 3-or the 9(ll)enolate, converting this into an enol ester and reacting thelatter with an electrophilic reagent to introduce the residue of anelectrophile, for example, a halogen atom. In some instances the enolateitself can be reacted directly to introduce a substituent in the 6- orll-position without intermedial-y formation of an enol ester and the keystep in our new method is, in fact, the selective enolisationpredominantly either at the 3- or the 9(ll)position. The new methodprovides a particularly effective method of introducing substituents atthe hindered 9-position.

Attempts to prepare enol esters from steroid 1,4-diene- 3,11-diones bytreatment with a strong base to the enolate, followed by quenching ofthe enolate anion with an acylating reagent have previously yieldedmixtures of the 3- and the 9(ll)derivatives, with consequentdifficulties of separation. Our researches have now succeeded inelucidating the mechanism of the enolisation reaction and have enabledus to formulate the conditions whereby either the 3-enolate or the9(ll)enolate is formed predominantly.

While we do not wish to be bound by theoretical considerations, it isbelieved that on reaction of the 1,4-

3,705,893 Patented Dec. 12, 1972 diene-3,l1-dione with a strong base, aproton is transferred from the 6-carbon atom to the base, yieldinginitially the 3-enolate, the removal of a proton from the 9- carbon atomto form the 9(ll)enolate being strongly sterically hindered. The3-lithium-enolates are stable, and do not enter into the subsequentreactions described below but other 3-alkali metal-enolates, in thepresence of steroid l,4-diene-3,11-dione, tend to rearrange to yield the9(ll)enolate which appears to be more stable. The rearrangement appearsto be bimolecular, one molecule of 3-enolate reacting with one moleculeof -3,l1-dione to yield one molecule of regenerated -3,1l-di0ne and onemolecule of 9(ll)enolate. Thus unreacted -3,11-di0ne need only bepresent in a catalytic quantity since it is constantly regenerated.However, the bimolecular rearrangement is considerably slower than theenolisation and if an excess of base is added, the -3 enolate will beformed quantitatively before rearrangement can take place to asignificant extent. Furthermore, at very low temperatures, for example,below 50 C., the bimolecular rearrangement is so slow as to benegligible and at such temperatures substantially only 3-enolate isapparently present (as demonstrated by forming an enol ester). It canthus be seen that if the reaction conditions are selected so that theinitially formed 3-enolate cannot come in contact with the unreacteddione, or can only contact the dione under conditions in whichrearrangement will not occur, the 3-enolate is obtained as reactionproduct, whereas if the reaction conditions are selected so that theinitially formed 3-enolate can contact unreacted dione under conditionsin which rearrangement can occur, the 9(ll)enolate is obtained.

If one equivalent of the dione is slowly added to a solution containingslightly more than one equivalent of the base, free dione is neverpresent to a significant extent and only the 3-enolate is formed. On theother hand, if very slightly less than one equivalent of base is slowlyadded to a solution of one equivalent of dione, so that some unreacteddione is always present, predominantly 9(ll)enolate is formed, provided,of course, that sllfficient time is allowed for the bimolecularrearrangement to take place at the selected reaction temperature which,clearly, is desirably not unduly low.

As indicated above, if the reaction of base and dione is effected at avery low temperature, for example about 70 C. to C., predominantly the3-enolate will be obtained. Our new method is to be contrasted withpreviously attempted enolisations of l,4-diene-3,11-diones by thestraight-forward addition of an excess of a base to the dione in asingle batch whereby the rapid enolisation removed all the free dionebefore rearrangement was complete and a substantial quantity of3-enolate always remained at the time of ester formation.

According to the present invention therefore we provide a process forthe selective 3- or 9( l1)-enolisation of a steriod 1,4-diene-3,11-dionein which the 1,4-dione-3,l1- dione is treated under substantiallyoxygen-free and anhydrous conditions in a non-hydroxylic solvent with analkali metal base other than a lithium base soluble in the solvent toform the 3-enolate; when the 9(ll)enolate is required, the dione innon-enolised form being allowed or caused either subsequently orsimultaneously to react with the 3-enolate initially formed; when the3-enolate is required the reaction being carried out at a temperaturebelow 50 C. or the reaction being carried out in a manner wherebycontact between the 3-enolate and unreacted dione is reduced or avoided.

An alkali metal base, that is a sodium, potassium, rubidium or caesiumbase, acting as a strong nucleophile under anhydrous non-hydroxylicconditions is required to abstract the desired proton from the 6- and9-position.

Alkali metal hydrides; amides; alkylamides, e.g. sodium or potassiumdiisopropylamide; triarylmethyls and acetylides or other non-hydroxylicalkali metal derivatives which do not react with ketones may be used asbase. Particularly preferred bases are the alkali metal bistertiarysilylamides particularly alkali metal bistrialkylsilylamides such asbistrimethylsilylamides.

The reaction conditions, as stated above, should be oxygen-free andanhydrous; and atmosphere of a dry inert gas such as nitrogen or,preferably, argon is desirable. The non-hydroxylic solvent used shouldbe dry and further should dissolve at least part of the reactant steroiddione and base.

Ethers are useful in this respect and it is particularly advantageous touse cyclic ethers such as tetrahydrofuran, which may conveniently beused with aromatic hydrocarbons such as benzene or toluene.

The reaction temperature, where low temperatures are not required toavoid bimolecular rearrangement, is preferably from -50 C. to 100 C.,advantageously ambient temperature e.g. to 25 C.

Where 9(11)-enolate is required, it may be convenient to effect thereaction under conditions leading to formatron of a 3-enolate forexample a sodium 3-enolate, and to add to the initial reaction productsa quantity of the dione sufiicient to efiect the bimolecularrearrangement to the 9(11)-enolate.

The enolates formed are advantageously, as indicated above, converteddirectly into enol esters. Thus, for example, the reaction with thealkali metal base may be conveniently quenched and the correspondingester pro,- duced, by treating the reaction mixture in situ with anacylating agent, e.g. a reactive ester, for example, the acid halide, ormore particularly, the anhydride, of an organic acid such as analiphatic, araliphatic or aromatic carboxylic or sulphonic acid. It isparticularly preferred to use the anhydride of an aromatic carboxylicacid and, for example, quenching the reaction with benzoic anhydriedyields the desired 3- or 9(l1)-enol benzoate, in virtually quantitativeyield. Acetic anhydride similarly yields the corresponding acetates.This quenching procedure is particularly useful in worikng up reactionscarried out at very low temperatures, the rapid acylation eifectivelypreventing any loss of the 3-enol.

Any steroid l,4-diene-3,ll-dioue can be enolised by the processaccording to the present invention, especially corticosteroids of theprednisone type and suitably substituted progesterone and androstanederivatives. Particularly desirable enolates are formed from prednisoneBMD ,(17,20:20,21-bismethylenedioxyprednisone) and its 160: andl6fi-meth'yl analogues, n -ll-ketoprogesterone ethylene ketal andandrostane-l,4-diene-3,l1,17-trione-l7- monoethylene ketal.

The 9(l1)-enol esters described above are novel compounds and comprise afeature of the invention. The benzoate esters are preferred and amongthe compounds especially useful are included the 9(1l)-enol benzoates ofcorticosteroids of the prednisone type, particularly 17,20:20,21bismethylenedioxyprednisone 9(ll)-enol benzoate.

The 3- and 9(ll)-enol esters or the parent 3- and 9(l1)- enolates are,as indicated previously, particularly useful as starting compounds forelectrophilic substitution reactions at 6- or 9-positions. Thus, forexample, reaction with sources of positive halogen such as molecularchlorine or bromine, introduces a halogen atom at the 6- or 9'position.It is particularly useful to introduce fluorine, especially at the9a-position, by reacting an enolate or enol ester with an electrophilicfluorinating agent, such as perchloryl fluoride, or a hypofiuoritereagent such as trifluoromethyl hypofiuorite. The method according tothe invention thus allows 9cz-fill0l0 prednisone or a 16mmethyl orl6fl-methyl derivative to be prepared directly from prednisone or itsl-methyl derivatives.

By the term steroid as used herein we mean substances which possess thecyclopentanoperhydrophenanthrene structure and which may carry varioussubstituents. Apart from the 3- and ll-oxo groups and the double bondsin the 1,2- and 4,5-positions, the steroid may carry substituents at the10- and l3-positions, e.g. alkyl groups such as the methyl groupsusually present in the andro stanes and pregnanes; at the 16::- orISfl-position, for example, alkyl, e.g. methyl, or alkylene, e.g.methylene, groups, or halogen atoms and at the 17-position, for example,a hydroxy or acyloxy group which may be present together with or as analternative to an aliphatic group such as an acyl group e.g. the acetylor fi-hydroxyacetyl group. Where an enolisable oxo group is present suchas in the 20-0xo pregnanes of the corticoid type, this should beprotected prior to the reaction, for example, by formation of a ketal,or orthoester derivative. In particular, the l7m-hydroxy-20-oxo 21hydroxy-pregnane structure which occurs in the corticosteroids of theprednisone and betarnethasone type, may be protected by formation ofbis-methylenedioxide derivatives.

Where the steroid 1,4-diene-3,ll-dione used as starting materialcontains groups which may be hydrolysed under the basic conditionspresent in the reaction according to the invention, it is necessary toensure a sufficient excess of base to complete the enolisation, thehydrolysed group, if desired, being subsequently restored to itsoriginal form. For example, acyloxy groups such as esterified hydroxygroups, may be hydrolysed under the reaction conditions and should then,if desired, be re-esterified.

The following examples are given by way of illustration:

(A) PREPARATION OF 3-ENOLATES CHARAG T ERISED AS THEIR 3-BENZOATESExample 1: Reaction at low temperature Prednisone BMDl7,20:20,2l-bismethylenedioxyprednisone) 200 mg., 0.5 mmole) wasdissolved in freshly purified THF (tetrahydrofuran) (6 ml.) and sealedin a septum bottle under argon. The steroid solution was then cooled to-78 C. Sodium bistrimethylsilylamide (549.5 mg., 3.0. mmoles) in THF (5ml.) at 78 C. was added to the steroid solution and the reaction allowedto proceed for 3 hours. Benzoic anhydride (crystallised fromhexane2benzene; 452 mg., 2.0. mmoles) was added to the reaction mixturewhich was then allowed to warm up to room temperature. The mixture wasthen washed with water, dried and evaporated to dryness in vacuo and theresidue taken up in chloroform. The crude mixture was purified bypreparative thin layer chromatography on eluting with chloroform:ether(60:40 VOL/vol.) to yield the 3-enol benzoate (203 mg., 0.4 mmole; 80%;M.P. 226- 228 C.; [a] ='-182).

Example 2: Slow addition of steroid to base Prednisone BMD (200 mg., 0.5mmole) in dry TI-IF (10 ml.) was added dropwise over 30 minutes withvigorous stirring to sodium bistrimethylsilylamide (120.3 mg., 0.55mmole) in THF (5 ml.) under argon, the mixture remaining at roomtemperature throughout the addition. The mixture was then stirred afurther 2 minutes and benzoic anhydride (452 mg., 2.0 mmoles) added. Themixture was then worked up as before to yield the 3-enol benzoate (207mg., 0.405 mmole; 82%). Use of triphenylmethylsodium (3 mol. equiv.) orsodium acetyl ide (5 mol. equiv.) yields the identical S-enol benzoate.Following this method, the 3-enol benzoates of 16amethyl prednisone BMD,l6;3-methylprednisone BMD, A I1-keto-progesterone-20-ethylene ketal andandrostanel,4-diene-3,ll,l7-trione 17-monoethylene ketal may beprepared.

(B) PREPARATION OF 9(11)-E'NOLATES CHAR- ACTERISED AS THEIR 9(11)-BENZOATES Example 3: Slow addition of base to steroid Sodiumbistrimethylsilylamide (165 mg., 0.9 mmole) in THF (5 ml.) was addeddropwise at room temperature over 30 minutes to A -prednisone BMD (200mg., 0.5 mmole) in THF (6 ml.) under argon. The reaction mixture wasstirred a further 2 minutes and then benzoic anhydride (452 mg., 2.0mmoles) added. The reaction mixture as then worked up as before to yieldthe 9(11)- enol benzoate (203 mg., 0.4 mmole; 80%; M.P. 290 293 C., [a]=+33.4). Following this method, the 9(l1)-enol benzoates of l6u-methylprednisone BMD, IGB-methyl prednisone BMD, A -1l-keto-progesterone-ZO-ethylene ketal and androstrane-1,4-diene-3,l1,17-monoethylene ketal maybe prepared. Use of triphenylmethylsodium (2 mol. equiv.) or sodiumacetylide (2 mol. equiv. dispersed in xylene/tetrahydrofuran) yields theidentical 9(11)-eno1 benzoate.

Example 4: Addition of unreacted steroid to a solution of the 3-enolateThe reaction of Example 1 was repeated allowing a reaction time of 4 /2hours. The solution of 3-enolate was allowed to warm up to roomtemperature and more prednisone BMD (300 mg., 0.75 mmole) in THF (9 ml.)was added. The reaction mixture was stirred at room temperature for afurther 6 minutes and then benzoic anhydride (452 mg., 2.0. mmoles) wasadded. The reaction mixture was worked up as before to yield the9(11)-enol benzoate (192 mg., 0.38 mmole; 76%; identical with theproduct of Example 3 (t.l.c.)).

Example 5: Reaction of prednisone BMD 9(11)-enol benzoate withtrifluoromethyl hypofluorite (CF OF) Prednisone BMD 9(11)-eno1 benzoate(500 mg.) was dissolved in a mixture of Freon (100 ml.) and methylenechloride (50 ml.) and reacted with CF OF in the presence of CaO (200mg.) under nitrogen at about 78 C. The crude product (572 mg.) waschromatographed over alumina (grade 3, 40 g.). Elution with benzene,followed by ether/benzene mixtures up to 10% ether, produced smallamounts of several non polar products (total weight 103 mg.) which werenot studied further. Elution with 20% ether/benzene yielded a series offractions containing two main components (A and B) resolved on t.l.c.,of which the more polar (A) was the more abundant. Earlier fractionscontaining a greater abundance of (B) (total weight 127 mg.) werecombined and absorbed onto a 20 x 20 x 0.1 cm. silica G thick layerchromatography plate. After elution thrice with 1% MeOH/CH Cl threezones were scraped from the plate and absorbed product was re-extractedusing several aliquots of 10% MeOH/CH Cl The next few fractions (97 mg.)were treated in a similar way. Comparison of the I. R. spectra andt.l.cs of the various zones indicated that A and B could bedistinguished by their characteristic carbonyl absorptions. Combinationof the appropriate fractions followed by crystallization from CH Cl/MeOH gave pure A (32 mg), M.P. 276-84 C. whose I.R., was superimposableon that of 9a-fluoro predm'sone BMD and which did not depress a mixedmelting point with an authentic sample. Combination of other fractionsand crystallization from CH CI /MeOH gave B (20 mg.). Recrystallizationfrom the same solvent gave heavy prisms (14 mg.), IR.

1750 (s.), 1670 (vs.), 1635 (m.), 1610 (w.), 1270 (vs.), 1210 (vs.)cm.-l. The analytical specimen had M.P. 130- 32" C., [01] +447 (c.=1.l).

Hydrolysis of B with methanolic sodium hydroxide yielded compound Asuggesting that B is 9oz-fill0l0-lloztrifiuoromethoxy-llfi-benzoyl-prednisolone BMD.

6 Example 6: 6,8-fluoro-prednisone BMD (9) Prednisone BMD 3-enolbenzoate (250 mg.) was dissolved in a mixture of Freon (40 ml.) andmethylene chloride (20 ml.) in the presence of calcium oxide 1740 (s.),1260 (s.) (benzoate), 1705 (s.) (ketone) cm.- Crystallization frommethylene chloride/ ether gave (9) (30 mg. 1st crop), LR.

CHC I "max.

1705 (s.) cm." (ketone), 1670 (vs.), 1625 (m.) dienone) cmr A secondcrop of mg. was also obtained.

What is claimed is:

1. A process for the selective 9(11)-enolisation of a 1,4-diene-3,l1-dione steroid of the androstane or pregnane series in whichthe 1,4-diene-3,l1-dione is treated under substantially oxygen-free andanhydrous conditions in a non-hydroxylic solvent with an alkali metalbase other than a lithium base soluble in the solvent, to form the 3-enolate; the dione in non-enolised form being allowed or caused eithersubsequently or simultaneously to react with the 3-enolate initiallyformed.

2. A process as claimed in claim 1 in which the base is abistrimethylsilylamide.

3. A process as claimed in claim 1 in which the temperature is from 50C. to 100 C.

4. A process as claimed in claim 1 in which very slightly less than oneequivalent of base is slowly added to a solution of one equivalent ofdione whereby some unreacted dione is always present and predominantly9(l1)-enolate is formed.

5. A process as claimed in claim 1 in which, where the 9(11)-enolate isrequired, the reaction is effected by adding to a 3-enolate a quantityof the dione sufiicient to effect the bimolecular rearrangement to the9(l1)-enolate.

6. A process as claimed in claim 1 in which the enolate formed isconverted directly into its enol ester by treatment of the reactionmixture in situ with an acylating agent selected from the groupconsisting of an aliphatic carboxylic acid halide, an araliphaticcarboxylic acid halide,an aromatic carboxylic acid halide, an aliphaticcarboxylic acid anhydride, an araliphatic carboxylic acid anhydride, anaromatic carboxylic acid anhydride, an aliphatic sulphonyl halide, anaraliphatic sulphonyl halide, an aromatic sulphonyl halide, an aliphaticsulphonic acid anhydride, an araliphatic sulphonic acid anhydride and anaromatic sulphonic acid anhydride.

7. A process as claimed in claim 6 in which the acylating agent isbenzoic or acetic anhydride.

8. A process as claimed in claim 1 in which the 1,4- diene-3,11-dionestarting material carries other enolisable keto groups in a protectedform.

9. A process as claimed in claim 1 in which the 9(1l)- enolate initiallyprepared, or an ester thereof, is subsequently reacted with ahalogenating reagent selected from the group consisting of bromine,chlorine, perchloryl fluoride and a hydrofiuorite reagent.

10. A process for electrophilic halogenation at the 9- position of asteroid in which the 9(l1)-enolate or -enol ester of a1,4-diene-3,11-dione steroid of the androstane or pregnane series isreacted with a halogenating reagent selected from the group consistingof bromine, chlorine, perchloryl fluoride and a hypofiuorite reagentwhereby the corresponding 9a-halogenosteroid l,4-diene-3,11-dione isformed.

11. A process as claimed in claim 6 in which the halogenating reagent istrifluoromethyl hypofluorite.

12. A process as claimed in claim 1 wherein the 1,4- diene-3,ll-dionestarting material is substituted at the 10- and l3-positions by hydrogenor an alkyl group, and at the 16aor 16,8-position by hydrogen or analkyl group.

13. A 9(1l)-cno1 benzoate or acetate of a l.4-diene-3,1 I- dione steroidof the androstane or pregnane series sub stituted at the 10- andl3-positions by an alkyl group and at the 1611- or l6 8-position byhydrogen or an alkyl group.

14. A compound of claim 24 selected from the group consisting of the9(11)-enol benzoate or acetate of 17,20:20,2l-bismethylenedioxy-prednis0ne and its lfia-rnethyl andl6fl-rnethyl analogues, of ll-keto-progesterone-ZO- No references cited.

ELBERT L. ROBERTS, Primary Examiner Y Us. c1. X.R. 260239.55 c, 397.45

